Despite advances in organ transplantation, transplant of an allograft organ can be hindered by organ rejection. Graft endothelial cells play crucial role in organ rejection because they express MHC class I and II molecules on the cell surface, which activate host alloreactive memory T cells. It has been demonstrated that reducing MHC class II expression on endothelial cells can reduce alloreactive CD4+ T cell activation, which can reduce graft immunogenicity. Therefore, I propose to deliver siRNA loaded nanoparticles to endothelial cells lining the blood vessels to accomplish non-toxic and sustained knockdown of MHC class II molecules, thereby eliminating memory CD4+ T cell activation and subsequent graft rejection. Aim 1 of this proposed research plan is to design a novel polymeric delivery vehicle for sustained delivery of siRNA to endothelial cells, followed by evaluation of the effect of siRNA-mediated knockdown of MHC II molecules on T cell response in vitro. In aim 2, I will design a perfusion system to deliver siRNA-loaded nanoparticles to endothelial cells in an isolated vessel before transplantation, and characterize the extent of MHC class II knockdown after perfusion. Through these aims, significant progress will be toward developing an siRNA-based strategy to prevent human transplant rejection.